Alternative titles; symbols
SNOMEDCT: 1296847007; ORPHA: 2169, 622; DO: 0112255;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.31 | Homocystinuria-megaloblastic anemia, cbl E type | 236270 | Autosomal recessive | 3 | MTRR | 602568 |
A number sign (#) is used with this entry because homocystinuria-megaloblastic anemia, cblE complementation type, is caused by homozygous or compound heterozygous mutation in the gene encoding methionine synthase reductase (MTRR; 602568) on chromosome 5p15.
Homocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase (MTR; 156570). Clinical features are somewhat variable, but include delayed psychomotor development, hypotonia, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE and CblG (250940) (Watkins and Rosenblatt, 1988). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (summary by Leclerc et al., 1996).
CblG is caused by mutation in the MTR gene.
Schuh et al. (1984) described a 'new,' presumably inborn, error of metabolism due to a defect in cobalamin metabolism. The infant boy, born of unrelated parents, presented with megaloblastic anemia and homocystinuria but without methylmalonic aciduria and showed severe developmental delay. The authors presented evidence to suggest an impairment in the formation or accumulation of methylcobalamin but not of adenosylcobalamin. Treatment with hydroxocobalamin, but not with cyanocobalamin and folic acid, resulted in rapid clinical and biochemical improvement. Cultured fibroblasts showed an absolute growth requirement for methionine and other features indicating an intracellular defect of methionine synthesis. Rosenblatt et al. (1984) performed studies on fibroblasts from the patient reported by Schuh et al. (1984). Labeled cobalamin was bound in appropriate amounts to the 2 vitamin B12-dependent enzymes, methionine synthase and methylmalonyl-CoA mutase, but intracellular methylcobalamin levels were decreased compared to controls. Although methionine synthase activity was normal in cell extracts under normal conditions, activity was decreased under suboptimal reducing conditions and intact cells were unable to synthesize adequate methionine for growth. Rosenblatt et al. (1984) suggested that the defect was in a reducing system normally responsible for maintaining enzyme-bound cobalamin in a state necessary for proper function of methionine synthase. Rosenblatt et al. (1985) described a second affected son in this family and found that the parents had a partial defect in the incorporation of (14C)methyltetrahydrofolate into methionine by their fibroblasts. The second affected sib, who was identified prenatally and treated with hydroxocobalamin (OH-B12), showed normal growth and development at age 6 months.
Fowler et al. (1997) stated that 5 males with the cblE defect had been reported and 2 females were known anecdotally. They reported the first detailed study of a female patient with cblE disease. The patient had folate-responsive homocystinuria and megaloblastic anemia. Clinical progress over 17 years was recorded. Before treatment, major findings were microcephaly, psychomotor retardation, episodic lowered consciousness, megaloblastic anemia, increased plasma free homocystine, low plasma methionine, and increased excretion of formiminoglutamate. On high-dose folic acid, biochemical abnormalities such as formiminoglutamate excretion and homocystinuria nearly normalized, but clinical and hematologic abnormalities remained. On replacement of folate with methylcobalamin, alertness, motor function, speech, and electroencephalogram improved, and although biochemical features were similar, the mean corpuscular volume increased. The best control was observed on a combination of folate and methylcobalamin. She remained severely mentally retarded at age 17 years.
Zavadakova et al. (2005) reported 9 European patients with cblE type homocystinuria. They presented between 2 weeks and 3 years of age (median age, 4 weeks) with anemia, which was macrocytic in only 3 patients, and with neurologic involvement in all but 2 patients. Bone marrow examination performed in 7 patients showed megaloblastic changes in all but 1. All patients exhibited moderate to severe hyperhomocysteinemia, while clearly reduced methionine was observed only in 4 cases.
The mode of inheritance of HMAE is autosomal recessive (Zavadakova et al., 2005).
In 2 sibs with homocystinuria-megaloblastic anemia due to defects in cobalamin metabolism, cblE type, originally reported by Schuh et al. (1984) and Rosenblatt et al. (1985), Leclerc et al. (1998) identified a heterozygous truncating mutation in the MTRR gene (602568.0001). A second mutation was not found. Another unrelated patient carried a different truncation mutation (602568.0002); a second mutation was not found.
Zavadakova et al. (2002) reported 2 additional patients with cblE type homocystinuria, 1 of whom was compound heterozygous for 2 novel mutations (602568.0004 and 602568.0005) and the other homozygous for a 140-bp insertion (602568.0006) in the MTRR gene.
In 9 European patients with cblE type homocystinuria, Zavadakova et al. (2005) identified pathogenic biallelic mutations in the MTRR gene (see, e.g., 602568.0007). Transfection of fibroblasts of cblE patients with a wildtype MTRR minigene expression construct resulted in a significant increase of approximately 4-fold in methionine synthesis, indicating correction of the enzyme defect. Zavadakova et al. (2005) found no obvious genotype-phenotype correlation except for a link between a milder predominantly hematologic presentation and homozygosity for the S454L mutation (602568.0007).
Fowler, B., Schutgens, R. B. H., Rosenblatt, D. S., Smit, G. P. A., Lindemans, J. Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cbl E disease). J. Inherit. Metab. Dis. 20: 731-741, 1997. [PubMed: 9427140] [Full Text: https://doi.org/10.1023/a:1005372730310]
Leclerc, D., Campeau, E., Goyette, P., Adjalla, C. E., Christensen, B., Ross, M., Eydoux, P., Rosenblatt, D. S., Rozen, R., Gravel, R. A. Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders. Hum. Molec. Genet. 5: 1867-1874, 1996. [PubMed: 8968737] [Full Text: https://doi.org/10.1093/hmg/5.12.1867]
Leclerc, D., Wilson, A., Dumas, R., Gafuik, C., Song, D., Watkins, D., Heng, H. H. Q., Rommens, J. M., Scherer, S. W., Rosenblatt, D. S., Gravel, R. A. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria. Proc. Nat. Acad. Sci. 95: 3059-3064, 1998. [PubMed: 9501215] [Full Text: https://doi.org/10.1073/pnas.95.6.3059]
Rosenblatt, D. S., Cooper, B. A., Pottier, A., Lue-Shing, H., Matiaszuk, N., Grauer, K. Altered vitamin B12 metabolism in fibroblasts from a patient with megaloblastic anemia and homocystinuria due to a new defect in methionine biosynthesis. J. Clin. Invest. 74: 2149-2156, 1984. [PubMed: 6511919] [Full Text: https://doi.org/10.1172/JCI111641]
Rosenblatt, D. S., Cooper, B. A., Schmutz, S. M., Zaleski, W. A., Casey, R. E. Prenatal vitamin B-12 therapy of a fetus with methylcobalamin deficiency (cobalamin E disease). Lancet 325: 1127-1129, 1985. Note: Originally Volume I. [PubMed: 2860337] [Full Text: https://doi.org/10.1016/s0140-6736(85)92433-x]
Schuh, S., Rosenblatt, D. S., Cooper, B. A., Schroeder, M.-L., Bishop, A. J., Seargeant, L. E., Haworth, J. C. Homocystinuria and megaloblastic anemia responsive to vitamin B-12 therapy. New Eng. J. Med. 310: 686-690, 1984. [PubMed: 6700644] [Full Text: https://doi.org/10.1056/NEJM198403153101104]
Watkins, D., Rosenblatt, D. S. Genetic heterogeneity among patients with methylcobalamin deficiency. J. Clin. Invest. 81: 1690-1694, 1988. [PubMed: 3384945] [Full Text: https://doi.org/10.1172/JCI113507]
Zavadakova, P., Fowler, B., Suormala, T., Novotna, Z., Mueller, P., Hennermann, J. B., Zeman, J., Vilaseca, M. A., Vilarinho, L., Gutsche, S., Wilichowski, E., Horneff, G., Kozich, V. cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression. Hum. Mutat. 25: 239-247, 2005. Note: Erratum: Hum. Mutat. 26: 590 only, 2005. [PubMed: 15714522] [Full Text: https://doi.org/10.1002/humu.20131]
Zavadakova, P., Fowler, B., Zeman, J., Suormala, T., Pristoupilova, K., Kozich, V. CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in 2 families. J. Inherit. Metab. Dis. 25: 461-476, 2002. Note: Erratum: J. Inherit. Metab. Dis. 26: 95 only, 2003. [PubMed: 12555939] [Full Text: https://doi.org/10.1023/a:1021299117308]